Molecular docking and dynamics of Nickel-Schiff base complexes for inhibiting β-lactamase of .

In recent years, multidrug-resistance has become a primary concern in the treatment and management of tuberculosis, an infectious disease caused by . In this context, searching new anti-tuberculosis agents particularly targeting the β-lactamase (BlaC) is reported to be promising as this enzyme is one of the key player in the development of multidrug resistance. This study reports the design of some Nickel (Ni) based tetradentate NO Schiff bases, employing density functional theory. All analogs are optimized at B3LYP/SDD level of theory. Dipole moment, electronic energy, enthalpy, Gibbs free energy, HOMO-LUMO gap, and softness of these modified drugs are also investigated. Molecular interactions between designed ligands and BlaC have been analyzed by molecular docking approach, followed by molecular dynamics (MD) simulation. All designed compounds show low HOMO-LUMO gap, while addition of halogen increases the dipole moment of the compounds. Docking and MD simulation investigations reveal that the designed compounds are more potent than standard inhibitor, where Ile117, Pro290, Arg236 and Thr253 residues of BlaC are found to play important role in the ligand binding. Through MD simulation study, the best binding compound is also observed to form stable complex by increasing the protein rigidness. The ADME/T analysis suggests that modified drugs are less toxic and shows an improved pharmacokinetic properties than that of the standard drug. These results further confirm the ability of Ni-directed Schiff bases to bind simultaneously to the active site of BlaC and support them as potential candidates for the future treatment of tuberculosis disease.